Application of alkyl acid compound in preparation of medicine for regulating ethanol autonomous intake preference

Abstract

The invention discloses an application of an alkyl acid compound in preparation of a medicine for regulating ethanol autonomous intake preference. The invention also discloses a pharmaceutical composition for adjusting the ethanol autonomous intake preference, and the pharmaceutical composition comprises the alkyl acid compound or the pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier and / or excipient. The application of the alkyl acid compound in preparing the medicine for adjusting the ethanol autonomous intake preference is provided for the first time, and animal experiments show that single injection of propofol into the tail vein of a mouse can continuously inhibit the ethanol autonomous intake preference of the mouse. The active ethanol intake absolute amount of mice and the relative ethanol intake proportion relative to the water intake amount can be obviously reduced, and the inhibition effect can last for at least 6 days.

Description

Technical Field

[0001] The invention relates to use of an alkyl acid compound in preparing a medicine for regulating autonomous ethanol intake preference, and belongs to the technical field of medicines. Background Art

[0002] Alcohol is a product of human civilization. People generally drink alcohol to socialize, cope with stress, and reduce negative emotions to a certain extent. However, when the time and amount of drinking reach a certain limit, drinkers may develop compulsive drinking behavior and develop somatization and withdrawal symptoms. This situation is called alcohol dependence or alcohol addiction. Excessive drinking may cause physical diseases, such as cirrhosis, and mental diseases, such as anxiety and depression, and even lead to suicide. According to statistics from the World Health Organization, about 8.6% of men and 1.7% of women in the world suffer from alcohol dependence. Only one-fifth of patients worldwide receive formal treatment for alcohol addiction, and the stubbornness and relapse of alcohol dependence make its cure rate even lower. At present, the treatment of alcohol addiction mainly relies on psychological cognitive therapy, and severe cases are supplemented with drug treatment. However, drugs used to treat alcohol addiction often have limitations such as unsatisfactory effects, the need to insist on daily medication, and multiple side effects. These limitations make the development of alcohol addiction drugs based on new targets and the exploration of new alcohol addiction properties of known drugs of great practical significance. Summary of the invention

[0003] The main purpose of the present invention is to provide a use of an alkyl acid compound in the preparation of a drug for regulating the preference for spontaneous ethanol intake, so as to make up for the deficiencies of the prior art.

[0004] Another object of the present invention is to provide a pharmaceutical composition for regulating voluntary ethanol intake preference.

[0005] In order to achieve the above-mentioned invention object, the technical solution adopted by the present invention includes:

[0006] The embodiment of the present invention provides a use of an alkyl acid compound in preparing a medicine for regulating the spontaneous ethanol intake preference.

[0007] The embodiment of the present invention also provides a pharmaceutical composition for regulating the preference for spontaneous ethanol intake, which comprises an alkyl acid compound or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier and / or excipient;

[0008] Wherein, the pharmaceutically acceptable derivative is selected from at least one of pharmaceutically acceptable salts, polymorphs, co-crystals, radiolabeled forms and combinations thereof.

[0009] Compared with the prior art, the beneficial effect of the present invention lies in that: the present invention proposes for the first time the use of alkyl acid compounds in the preparation of drugs for regulating the preference for spontaneous ethanol intake, and animal experiments show that a single injection of propofol into the tail vein of mice can continuously inhibit the mice's spontaneous ethanol intake preference, which is specifically manifested in that: the administration of the aforementioned compound can significantly reduce the absolute amount of active ethanol intake by mice and the relative proportion of ethanol intake compared to the amount of drinking water, and the inhibitory effect can last for at least 6 days. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0011] Figure 1 is a graph showing the relative preference of mice for active intake of 10% ethanol in a typical embodiment of the present invention;

[0012] Figure 2 is a graph showing the absolute content of 10% ethanol actively taken up by mice in a typical embodiment of the present invention;

[0013] Figure 3 is a graph of the total amount of fluid taken up voluntarily by mice in a typical embodiment of the present invention;

[0014] Figure 4a-4b The figure is a graph of the absolute amount of food actively ingested by mice and the body weight of mice in a typical embodiment of the present invention. DETAILED DESCRIPTION

[0015] In view of the defects of the prior art, the inventor of this case has proposed the technical solution of the present invention after long-term research and extensive practice. The technical solution of the present invention will be described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0016] Specifically, as one aspect of the technical solution of the present invention, the alkyl acid compounds involved therein are used in the preparation of drugs for regulating the preference for spontaneous ethanol intake.

[0017] In some preferred embodiments, the alkyl acid compound includes propofol, but is not limited thereto.

[0018] Furthermore, the propofol has a structure as shown in the following formula:

[0019]

[0020] Furthermore, the propofol is also known as 2,6-diisopropylphenol or propofol.

[0021] In some preferred embodiments, when the drug acts on a mouse model, the drug can at least reduce the absolute amount of active ethanol intake by the mouse.

[0022] In some preferred embodiments, when the drug acts on a mouse model, the drug inhibits the mouse from actively ingesting ethanol for more than 6 days.

[0023] Furthermore, the ethanol used is an ethanol solution with a volume fraction of 5 to 20%.

[0024] The mouse experiment of regulating the preference for ethanol autonomous intake in the present invention refers to the relative percentage and absolute amount of alcohol autonomously ingested by mice in a free state when facing water and 10% ethanol (volume fraction) provided at the same time; animal experiments show that a single injection of propofol into the tail vein of mice can continuously inhibit the preference of mice for autonomous intake of ethanol, which is specifically manifested as follows: the administration of the aforementioned compound can significantly reduce the absolute amount of active ethanol intake of mice and the relative proportion of ethanol intake compared to the amount of drinking water, and the inhibitory effect can last for at least 6 days. Propofol can reduce the relative preference of mice for active intake of 10% ethanol. Propofol can reduce the absolute content of active intake of 10% ethanol by mice. Propofol does not affect the total amount of liquid autonomously ingested by mice. Propofol does not affect the absolute amount of active food intake by mice and the weight of mice. It should also be pointed out that when alcohol-dependent mice use the aforementioned drugs once, the lasting effect after a single dose can maximize the extension of the medication cycle of the body and reduce the impact on the quality of life. In particular, propofol reduces the active desire of mice to drink, rather than forcibly removing alcohol, and has a comfort feature.

[0025] Another aspect of the embodiments of the present invention further provides a pharmaceutical composition for regulating ethanol spontaneous intake preference, which comprises an alkyl acid compound or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier and / or excipient;

[0026] Wherein, the pharmaceutically acceptable derivative is selected from at least one of pharmaceutically acceptable salts, polymorphs, co-crystals, radiolabeled forms and combinations thereof.

[0027] Further, the carrier and / or excipient can be any known pharmaceutically acceptable carrier and excipient for those skilled in the art suitable for such use. The "pharmaceutical carrier" described in this specification has a meaning well known to those skilled in the art, and can include any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, similar substances and combinations thereof.

[0028] In some preferred embodiments, the alkyl acid compound includes propofol, but is not limited thereto.

[0029] In some preferred embodiments, when the pharmaceutical composition acts on a mouse model, the pharmaceutical composition can at least reduce the absolute amount of active ethanol intake by the mouse.

[0030] In some preferred embodiments, when the pharmaceutical composition acts on a mouse model, the pharmaceutical composition inhibits the mouse's active intake of ethanol for more than 6 days.

[0031] Furthermore, the ethanol used is an ethanol solution with a volume fraction of 5 to 20%.

[0032] Furthermore, the dosage form of the pharmaceutical composition includes any one of injection, oral solution, capsule, tablet, and granule.

[0033] The term "pharmaceutically acceptable salt" as used herein refers to salts that are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reaction or other problems or complications within the scope of sound medical judgment, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, and the contents are incorporated by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic acids and bases and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed of amino groups with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or salts formed by using other methods in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, gluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hydroiodide, 2-hydroxyethanesulfonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like.

[0034] As used herein, "pharmaceutically acceptable salts" refer to forms of the disclosed compounds in which the parent compound is modified by preparing acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, such as those formed from non-toxic inorganic or organic acids. Such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid.

[0035] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic sites by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two; typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are used.

[0036] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the technical solution of the present invention is further described in detail below in conjunction with the accompanying drawings and several preferred embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0037] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0038] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources, for example:

[0039] 1. Experimental steps

[0040] 1. Experimental Animals:

[0041] C57BL / 6J mice were purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd. and bred at Xuzhou Medical University. Mice were housed in a standard animal room with a temperature of 23±2°C and a humidity of 40±10%, a 12h / 12h (lighting on at 8:00), and free access to food. This experiment was approved by the Animal Ethics Committee of Xuzhou Medical University and was performed in strict accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.

[0042] 2. Reagents:

[0043] Physiological saline was purchased from Shandong Kelun Pharmaceutical Co., Ltd.; propofol was purchased from Sichuan Guorui Pharmaceutical Co., Ltd.

[0044] 3. Experimental design:

[0045] Propofol was administered systemically via tail vein injection at a dose of 25 mg / kg. Mice were returned to the cage after injection, and various indicators were measured later. The main measurement indicators of this experiment were collected under the classic "two-bottle voluntary drinking model", which is specifically described as follows: mice moved freely in the cage, and two bottles of liquid were supplied to the mice during the experiment, one bottle was ordinary drinking water, and the other was a 10% ethanol solution. Mice freely drank water or ethanol according to individual preferences. The experimenter weighed the consumption of the two bottles of liquid once every 24 hours, and swapped the positions of the two bottles of liquid to avoid possible position preference. The data were statistically analyzed once every 48 hours, where: voluntary ethanol intake preference = ethanol solution intake weight / (ethanol solution intake weight + water intake weight) x 100%; the absolute amount of voluntary ethanol intake was described as the absolute content of ethanol intake per kilogram of body weight of mice in 24 hours; the total amount of voluntary liquid intake was described as the total mass of all liquids ingested per kilogram of mice in 24 hours; the absolute amount of voluntary food intake was described as the total number of grams of food ingested per kilogram of mice in 24 hours.

[0046] 4. Data Analysis:

[0047] All values ​​are expressed as mean ± standard error (SEM). For data that meet normal distribution, two-sided two-independent sample t-test was used for comparison between two groups, and two-way analysis of variance was used for comparison between multiple groups. P < 0.05 was considered statistically significant.

[0048] 2. Experimental Results

[0049] 1. Propofol can reduce the relative preference of mice for active intake of 10% ethanol

[0050] The free choice of mice in the scenario of facing water and ethanol solution at the same time can fully reflect the mice's willingness to consume alcohol. The most important indicator is the percentage of the mice's intake of the two liquids. The inventors of this case continuously observed the mice's preference for ethanol solution after injecting physiological saline or propofol into the tail vein. The results are as follows Figure 1 As shown: Compared with the mice injected with normal saline, the preference of mice in the propofol group for spontaneous ethanol ingestion was significantly reduced after a single injection of propofol, and the inhibitory effect lasted for at least 6 days, indicating that a single systemic administration of propofol can significantly and persistently reduce the willingness of mice to spontaneously ingest ethanol.

[0051] 2. Propofol can reduce the absolute content of 10% ethanol active intake in mice

[0052] The absolute amount of ethanol ingested by mice is another key indicator for evaluating whether propofol can affect the ethanol reactivity of mice. The actual absolute amount of ethanol ingested by mice was continuously observed after injection of saline or propofol into the tail vein. Figure 2As shown: Compared with the mice injected with normal saline, the absolute content of voluntary ethanol ingestion by mice in the propofol group after a single injection was significantly reduced, and the inhibitory effect lasted for at least 6 days, indicating that a single systemic administration of propofol can significantly and persistently reduce the absolute content of voluntary ethanol ingestion by mice.

[0053] 3. Propofol does not affect the total amount of fluid that mice voluntarily ingest

[0054] In order to explore whether the inhibitory effect of propofol on ethanol intake in this case was indirectly caused by the general inhibition of liquid intake, the total amount of all liquids ingested by mice was continuously observed after the tail vein injection of normal saline or propofol. Figure 3 As shown: Compared with the mice injected with normal saline, the total amount of fluid intake by mice in the single propofol injection group was roughly the same, with no statistical significance, indicating that systemic administration of propofol does not restrict ethanol intake by generally reducing fluid intake, but directly affects the mice's preference response to ethanol.

[0055] 4. Propofol does not affect the absolute amount of food intake and body weight of mice

[0056] In order to exclude the possibility that the food intake of mice in this case may affect the amount of liquid drinking through thirst response, the food intake and body weight parameters of mice were observed after the tail vein injection of normal saline or propofol. Figure 4a-4b As shown: Compared with the mice injected with normal saline, the total amount of food consumed by the mice in the propofol group after a single injection was roughly the same ( Figure 4a ), and there was no statistically significant difference in body weight between the two groups of mice ( Figure 4b ), indicating that systemic administration of propofol did not affect the food intake and body weight of mice, suggesting that propofol specifically and directly affects the preference response of mice to ethanol.

[0057] In addition, the inventors of this case also referred to the aforementioned embodiments and conducted experiments with other raw materials, process operations, and process conditions described in this specification, and obtained relatively ideal results.

[0058] It should be understood that the technical solution of the present invention is not limited to the above-mentioned specific implementation cases. Any technical deformation made according to the technical solution of the present invention without departing from the scope of protection of the purpose of the present invention and the claims shall fall within the protection scope of the present invention.

Claims

1. Use of alkyl acid compounds in the preparation of a drug for regulating the preference for spontaneous ethanol intake.

2. The use according to claim 1, characterized in that: The alkyl acid compounds include propofol.

3. The use according to claim 1, characterized in that: When the drug acts on a mouse model, the drug can at least reduce the absolute amount of active ethanol intake of the mouse.

4. The use according to claim 1, characterized in that: When the drug acts on a mouse model, the drug inhibits the mouse from actively taking in ethanol for more than 6 days.

5. The use according to claim 3 or 4, characterized in that: The ethanol used is an ethanol solution with a volume fraction of 5 to 20%.

6. A pharmaceutical composition for regulating voluntary ethanol intake preference, characterized in that: It comprises an alkyl acid compound or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier and / or excipient; Wherein, the pharmaceutically acceptable derivative is selected from at least one of pharmaceutically acceptable salts, polymorphs, co-crystals, radiolabeled forms and combinations thereof.

7. The pharmaceutical composition according to claim 6, characterized in that: The alkyl acid compounds include propofol.

8. The pharmaceutical composition according to claim 6, characterized in that: When the pharmaceutical composition acts on a mouse model, the pharmaceutical composition can at least reduce the absolute amount of active ethanol intake of the mouse.

9. The pharmaceutical composition according to claim 6, characterized in that: When the pharmaceutical composition acts on a mouse model, the pharmaceutical composition inhibits the mouse from actively taking in ethanol for more than 6 days.

10. The pharmaceutical composition according to claim 6, characterized in that: The dosage form of the pharmaceutical composition includes any one of injection, oral solution, capsule, tablet and granule.

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